Nasal spray compositions

ABSTRACT

Aqueous nasal spray compositions comprising a medicament and an aqueous carrier comprising water soluble polymers selected from the group consisting of polyvinylpyrrolidone and mixtures thereof.

This is a continuation of application Ser. No. 09/434,075 filed Nov. 5,1999 now U.S. Pat. No. 6,316,483, which is a continuation of applicationSer. No. 09/163,638, filed Sep. 30, 1998 now abandoned, application Ser.No. 08/964,038, filed Nov. 4, 1997, which issued as U.S. Pat. No.5,897,858; which was a continuation of application Ser. No. 08/375,014,filed Jan. 19, 1995, now abandoned; which was a continuation-in-part ofapplication Ser. No. 08/191,402, filed Feb. 3, 1994, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to aqueous nasal compositions comprising amedicament in an aqueous carrier containing a water soluble polymerselected from the group of polyvinylpyrrolidone and mixtures thereof.The combination of water soluble polymers provides unexpected propertieswhich enhance medicinal efficacy and promotes organoleptic acceptance ofthe compositions.

One of the major hindrances to effective systemic absorption ofmedicaments such as chlorpheniramine maleate in the nose is due toanatomical features of the epithelium within the nasal cavity. Theconstant beating of the nasal cilia causes the mucus film to continuallymove toward the nasopharynx. This action, in about 8 to 10 minutes, willremove the medicament from the nasal mucosa reducing the time foreffective systemic absorption.

Certain medicaments are active topically and are not systemicallyabsorbed, such as the topically active nasal decongestant oxymetazolinehydrochloride. This medicament is a vasoconstrictor that increases nasalairway volume by reducing blood flow to the nasal capillary bed.Oxymetazoline hydrochloride also reduces blood flow to themuco-secreting cells and as a result reduces nasal secretions. Thisreduction of natural moisture replacement in conjunction with moisturevaporization due to increased air flow volume promotes drying of thenasal cavity. Loss of this protective mucosal film may result in anincreased occurrence in nasal sensitivity and associated burning andstinging.

It is known that when a combination of medicaments, such aschlorpheniramine maleate and oxymetazoline hydrochloride areincorporated into typical nasal spray formulations the occurrence ofnasal burning and stinging increases.

Nasal drying and the associated stinging within the nasal cavity is oneof the most common complaints of patients and consumers that use nasalspray products. Other common nasal product negative attributes includeodor, taste and the tendency of the product to run out of the nose.

We have surprisingly discovered that incorporation of a combination ofwater soluble polymers selected from the group consisting ofpolyvinylpyrrolidone, polyethylene glycol and mixtures thereof intonasal spray compositions provide enhanced medicinal efficacy andpromotes organoleptic acceptence of the compositions.

It is an object of the present invention to provide nasal spraycompositions exhibiting increased nasal retention of medicaments in thenasal cavity for enhanced topical or systemic activity.

Another object of the present invention is to provide nasal spraycompositions exhibiting reduced post nasal drip.

It is a further object of the present invention to provide nasal spraycompositions exhibiting increased moisturization in the nasal cavity.

A further object of the present invention is to provide nasal spraycompositions which reduce the potential of medicament induced stinging,burning, overdrying or irritation.

SUMMARY OF THE INVENTION

The present invention provides aqueous nasal spray compositionscomprising a medicament and an aqueous carrier containing a watersoluble polymer selected from the group consisting ofpolyvinylpyrrolidone and mixtures thereof.

The present invention provides aqueous nasal spray compositionscomprising an effective amount of a medicament in an aqueous carriercomprising:

0.50 to 15.00% by weight/volume of a water soluble polymer selected fromthe group consisting of polyvinylpyrrolidone and mixtures thereof;

0.00 to 15.00% by weight/volume of polyethylene glycol;

0.00 to 10.00% by weight/volume of a moisturizing agent or mixtures ofmoisturizing agents;

0.00 to 10.00% by weight/volume of an antioxidant;

0.001 to 0.10% by weight/volume of an antimicrobial preservative;

0.00 to 5.00% by weight/volume of an aromatic alcohol;

a sufficient amount of a pharmaceutically acceptable buffer to maintainthe pH of the composition within the range of about 4.0 to 8.0 and

QS water.

The present invention further provides a method of treating nasalconditions by administering to a nasal passage of a patient an aqueousnasal spray composition of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The aqueous nasal spray compositions of the present invention comprise amedicament in an aqueous carrier containing a water soluble polymerselected from the group consisting of polyvinylpyrrolidone and mixturesthereof.

Compositions of the present invention contain a therapeuticallyeffective amount of at least one pharmaceutically acceptable medicament.The medicament drug may be selected from a wide range of therapeuticagents and mixtures of therapeutic agents. Illustrative categories andspecific examples include, analgesics, such as ibuprofen and ketoprofen;antiasmatics, such as theophylline; antitussives, such as noscapine andchlophedinol hydrochloride; antihistamines, such as chlorpheniraminemaleate, loratadine, azatadine; antinauseant, such as dimenhydrinate;decongestants, such as oxymetazoline hydrochloride; various alkaloids,such as codeine sulfate and morphine; stimulants, such as nicotine;mucolytics, such as acetylcysteine and bromhexine.

The preferred medicaments, alone or in combination, includechlorpheniramine maleate and oxymetazoline hydrochloride.

The amount of oxymetazoline hydrochloride found sufficient to effectnasal decongestion is from about 0.001 to about 0.2% by wt/vol of dietotal composition. Ranges of 0.01 to 0.1% of the total composition areparticularly suitable. Typically, 0.05% by wt/vol is preferred foradults and children above five years of age.

The amount of chlorpheniramine maleate found sufficient for intranasalantihistamine action is from about 0.001 to about 2.0% by wt/vol of thetotal composition. Ranges of 0.1 to 0.5% by wt/vol is most preferable.

Various gums and polymers have been evaluated to determine thesuitability of such materials as bioadhesives to extend the nasalmuco-cilia clearance time of nasal spray formulations. Desiredproperties of a bioadhesive include solubility, clarity andcompatibility in a conventional nasal spray formulation. In addition,the nasal spray composition containing the bioadhesive material wasevaluated to determine the concentration effect on spray pattern andresultant mist properties.

It has been found that polyvinylpyrrolidone, a linear polymer of1-vinyl-2-pyrrolidone, hereinafter designated PVP, extends muco-ciliaclearance times of nasal spray compositions. Polyvinylpyrrolidone, alsoknown as Providone, is commercially available as a series of productshaving mean molecular weights ranging from about 10,000 to about700,000. The various products are marketed according to averagemolecular weights designated K-values; e.g. GAF Corporation supplies PVPhaving the following K-values:

K-value Average Molecular Weight 15 about  10,000 30 about  40,000 60about 160,000 90 about 360,000

The nasal spray compositions of this invention contain various grades ofpolyvinylpyrrolidone, i.e. K-15, K-30, K-60 and K-90. Thepolyvinylpyrrolidone ingredient may be present as one specific grade oras a combination of two or more grades.

The most preferable polymers of polyvinylpyrrolidone for thecompositions of this invention are PVP K-30 and PVP K-90.

The amount of polyvinylpyrrolidone present in the compositions of thisinvention is from about 0.50 to 15.00% by weight/volume of the totalcomposition. Ranges of 0.50 to 2.5% by weight/volume of the totalcomposition are particularly suitable and a range of 1.00 to 1.50% byweight/volume of the total composition being most preferable.

To evaluate the effect of polyvinylpyrrolidone on nasal muco-ciliaclearance time, a modified procedure was employed as disclosed by E.Puchelle, et al., in Acta Otolarynogol, 91, 297-303. (1981). Theprocedure utilized a concentrated sodium saccharin solution as theindicator. A 100 mcl dose of water-soluble polymer test solution wassprayed into the nose. After spraying, a cotton swab saturated withsaccharin solution was inserted into the nostril and wiped around theostuim depositing the saccharin onto the nasal mucosal lining. Theclearance time was defined as the time for deposit of saccharin in theostuim to the time the saccharin was tasted in the back of thethroat/mough.

Experimental results of this testing indicated that polyvinylpyrrolidonewould extend nasal muco-cilia clearance times. For example, it was foundthat incorporation of PVP K-90 at 0.25% would extend nasal muco-ciliaclearance times from the: normal 8 to 10 minutes to 20 to 25 minutes.

The use of water soluble polyethylene glycol (PEG) polymers in thecompositions of this invention promotes moisturization of the nasalspray compositions in the nasal cavity. Polyethylene glycol is a linearpolymer formed by the addition reaction of ethylene glycol with ethyleneoxide and are commercially available in average molecular weightsranging from about 200 to greater than 20,000. The commerciallyavailable grades of polyethylene glycol are marketed based on theaverage molecular weight, i.e. the grade nomenclature is identified withthe molecular weight. For example, PEG 400 represents material with anaverage molecular weight of 400 and the material with an averagemolecular of 600 is known as PEG 600. PEG 200, 300, 400, and 600 areclear viscous liquids at room temperature; PEG 900, 1000, 1450, 3350,4500 and 8000 are white, waxy solids.

The preferred polyethylene glycols for the compositions of thisinvention are PEG 400 to PEG 3350; the most preferred polyethyleneglycol is PEG 1450.

The amount of polyethylene glycol present in the compositions of thisinvention is from about 0.00 to 15.0% by weight/volume of the totalcomposition. Ranges of 0.5% to 10% by weight/volume of the totalcomposition are particularly suitable and a range of 2.5 to 5% byweight/volume is most preferable.

The compositions of the present invention may contain an aromaticalcohol selected from the group consisting of benzyl alcohol and phenylethyl alcohol. The amount of aromatic alcohol present in the compositionis from about 0 to 5.00% by weight/volume of the total composition.Ranges of 0.20-3.00% by weight/volume of the total composition areparticularly suitable, and a range of 0.25 to 1.00% by weight/volume ofthe total composition being most preferable.

The compositions of the present invention may contain moisturizingagent. Examples of moisturizing agents useful in the compositions ofthis invention include propylene glycol, glycerin and the like. Mixturesof such moisturizing agents are also useful in the compositions. Theamount of moisturizing agent present in the composition is from about 0to 10% by weight/volume of the total composition. Ranges of 1.00 to4.00% by weight/volume of the total composition are particularlysuitable, and a range of 1.5 to 3.50% by weight/volume of the totalcomposition being most preferable.

The compositions of the present invention may contain a pharmaceuticallyacceptable antioxidant, e.g. disodium EDTA. The amount of antioxidentpresent in the composition is from about 0 to 0.10% by weight/volume ofthe total composition. Ranges of 0.01 to 0.05% by weight/volume of thetotal composition are particularly suitable, and a range of 0.015 to0.030% by weight/volume of the total composition being most preferable.

The compositions of the present invention contains at least oneantimicrobial preservative in the range of 0.001% to about 0.3% byweight/volume of the composition. A typical suitable preservative whichfunctions as an antimicrobial agent includes the commercially availablepreservative, benzalkonium chloride in the range of about 0.02 to about0.025% by weight/volume.

The compositions of the present invention also include pharmaceuticallyacceptable buffers sufficient to adjust and maintain the pH of thecompositions of the present invention in the range of about 4.0 to about8.0, preferably about 5.5 to about 7.0 and 6.25 to 6.75 being mostpreferable. Typically suitable buffers include citrate, phosphate andglycine.

The nasal spray compositions of the present invention is manufactured ina conventional manner by thoroughly mixing the ingredients at ambient orelevated temperatures in order to achieve solubility of ingredientswhere appropriate.

All percentages are by weight/volume. The definitions of componentswhose chemical composition is not immediately clear from the name usedmay be found in the CTFA Cosmetic Ingredients Dictionary, 4th Edition,1991, published by Cosmetic Toiletry and Fragrance Association, Inc.,Washington, D.C.

The following examples describe in detail the invention. It will beapparent to those skilled in the art that modifications may be practicedwithout departing from the purpose and intent of this disclosure.

EXAMPLE 1

An aqueous nasal spray composition is prepared from the following:

INGREDIENTS % Wt/Vol Water QS Disodium EDTA 0.0200 Sodium PhosphateDibasic 0.0975 Sodium Phosphate Monobasic 0.5525 PVP K-90 0.2500 PVPK-30 1.0000 PEG 1450 2.5000 Benzyl Alcohol 0.2500 Benzalkonium Chloride0.0200 (17% solution) Chlorpheniramine Maleate 0.5000 OxymetazolineHydrochloride 0.0500

The solution is prepared according to the following procedure.

To any appropriate reaction container, add 70% of the water and heat to50° C. Add the following: sodium phosphate monobasic, sodium phosphatedibasic, disodium EDTA and benzyl alcohol to the water. Mix eachingredient addition for at least 5 minutes. With continued mixing addthe water soluble polymers, i.e. the polyvinylpyrrolidone (PVP) and thepolyethylene glycol (PEG). Mix each ingredient addition for at least 5minutes. With continued mixing add the oxymetazoline hydrochloride andchlorpheniramine maleate; mix each ingredient addition for at least 5minutes. While mixing, add the benzalkonium chloride 17% solution andmix for at least 5 minutes. With continued mixing, the solution iscooled to 30° C. Adjust the final batch volume with water, mix untiluniform and then filter using conventional filtration equipment.

EXAMPLE 2

An aqueous nasal spray composition is prepared from the following:

INGREDIENTS % Wt/Vol Water QS Disodium EDTA 0.0200 Sodium PhosphateDibasic 0.0975 Sodium Phosphate Monobasic 0.5525 PVP K-90 0.2500 PVPK-30 1.0000 PEG 1450 2.5000 Benzyl Alcohol 0.2500 Benzalkonium Chloride0.0200 (17% solution) Oxymetazoline Hydrochloride 0.0500

The composition is prepared according to the procedure in Example 1.

EXAMPLE 3

An aqueous nasal spray composition is prepared from the following:

INGREDIENTS % Wt/Vol Water QS Disodium EDTA 0.0200 Sodium PhosphateDibasic 0.0975 Sodium Phosphate Monobasic 0.5525 PVP K-30 3.0000 PEG 6005.0000 Benzyl Alcohol 0.2500 Benzalkonium Chloride 0.0200 (17% solution)Oxymetazoline Hydrochloride 0.0500 Chlorpheniramine Maleate 0.5000

The composition is prepared according to the procedure in Example 1.

EXAMPLE 4

An aqueous nasal spray composition is prepared from the following:

INGREDIENTS % Wt/Vol Water QS Disodium EDTA 0.0200 Sodium PhosphateDibasic 0.0975 Sodium Phosphate Monobasic 0.5525 PVP K-30 3.0000 PEG1450 5.0000 Benzyl Alcohol 0.2500 Benzalkonium Chloride 0.0200 (17%solution) Oxymetazoline Hydrochloride 0.0500 Chlorpheniramine Maleate0.5000

The composition is prepared according to the procedure in Example 1.

EXAMPLE 5

An aqueous nasal spray composition is prepared from the following:

INGREDIENTS % Wt/Vol Water QS Disodium EDTA 0.0200 Sodium PhosphateDibasic 0.0975 Sodium Phosphate Monobasic 0.5525 PVP K-90 0.1000 PVPK-30 3.0000 PEG 1450 2.5000 Propylene glycol 0.2500 BenzalkoniumChloride 0.1471 (17% solution) Oxymetazoline Hydrochloride 0.0500

The composition is prepared according to the procedure in Example 1.

EXAMPLE 6

An aqueous nasal spray composition is prepared from the following:

INGREDIENTS % Wt/Vol Water QS Disodium EDTA 0.0200 Sodium PhosphateDibasic 0.0975 Sodium Phosphate Monobasic 0.5525 PVP K-90 0.1000 PVPK-30 3.0000 PEG 1450 5.0000 Propylene Glycol 2.0000 Glycerin 0.1000Benzalkonium Chloride 0.1471 (17% solution) Oxymetazoline Hydrochloride0.5000

The composition is prepared according to the procedure in Example 1.

We claim:
 1. An aqueous nasal spray composition prepared by combiningingredients comprising oxymetazoline hydrochloride and two or morelinear polymers of 1-Vinyl-2-pyrrolidone having different averagemolecular weights.
 2. The composition claim 1 wherein one linear polymeringredient has an average molecular weight about 10,000.
 3. Thecomposition of claim 1 wherein one linear polymer ingredient has anaverage molecular weight about 40,000.
 4. The composition of claim 1wherein one linear polymer ingredient has an average molecular weightabout 160,000.
 5. The composition of claim 1 wherein one linear polymeringredient has an average molecular weight about 360,000.
 6. Thecomposition of claim 1 wherein one linear polymer ingredient has anaverage molecular weight about 40,000 and another linear polymeringredient has an average molecular weight about 360,000.
 7. Thecomposition of claim 1 wherein the concentration of oxymetazolinehydrochloride is about 0.01 to about 0.1 percent by weight/volume. 8.The composition of claim 1 wherein the total concentration of the linearpolymer ingredients is about 0.5 to about 15 percent by weight/volume.9. The composition of claim 1, further comprising as an ingredient anaromatic alcohol.
 10. The composition of claim 1, further comprising asan ingredient benzyl alcohol.
 11. The composition of claim 1, furthercomprising as an ingredient phenylethyl alcohol.
 12. The composition ofclaim 1, further comprising as an ingredient benzalkonium chloride. 13.The composition of claim 1, further comprising as an ingredient awater-soluble polyethylene glycol.
 14. The composition of claim 1,further comprising as an ingredient a moisturizing agent selected fromthe group consisting of propylene glycol, glycerin and a mixturethereof.
 15. An aqueous nasal spray composition prepared by combiningingredients comprising: 0.01 to 0.1 percent by weight/volume ofoxymetazoline hydrochloride: a linear polymer of 1-Vinyl-2-pyrrolidonehaving an average molecular weight about 40,000; a linear polymer of1-Vinyl-2-pyrrolidone having an average molecular weight about 360,000;and a water-soluble polyethylene glycol; the total concentration of thelinear polymer ingredients being about 0.5 to about 15 percent byweight/volume.
 16. The composition of claim 15, further comprising as aningredient an aromatic alcohol.
 17. The composition of claim 15, furthercomprising as an ingredient benzalkonium chloride.
 18. The compositionof claim 15, further comprising as an ingredient a moisturizing agentselected from the group consisting of propylene glycol, glycerin and amixture thereof.
 19. An aqueous nasal spray composition prepared bycombining ingredients comprising: 0.01 to 0.1 percent by weight/volumeof oxymetazoline hydrochloride; a linear polymer of1-Vinyl-2-pyrrolidone having an average molecular weight about 40,000; alinear polymer of 1-Vinyl-2-pyrrolidone having an average molecularweight about 360,000; a water-soluble polyethylene glycol; benzalkoniumchloride; and a moisturizing agent selected from the group consisting ofpropylene glycol, glycerin and a mixture thereof; the totalconcentration of the linear polymer ingredients being about 0.5 to about15 percent by weight/volume.